1. Technical Field
The invention relates to a composition comprising a neuronal nicotinic receptor ligand and an α4β2 allosteric modulator, a method of using the same, and a related article of manufacture.
2. Description of Related Technology
Neuronal nicotinic receptors, especially α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have been targeted for pain and various central nervous system diseases. Antisense knockdown of the α4 subunit was found to decrease the analgesic effect of agonists (Bitner R S, Nikkel A L, Curzon P, Donnelly-Roberts D L, Puttfarcken P S, Namovic M, Jacobs I C, Meyer M D, and Decker M W (2000) Brain Res. 871:66-74). Reduced antinociceptive responses to nicotine also is seen in α4 gene knockout animals (Marubio L M, Arroyo-Jimenez M D, Cordero-Erausquin M, Lena C, Le Novere N, d'Exaerde A D, Huchet M, Damaj M I, and Changeux J P (1999) Nature 398:805-810). Both α4 and β2 nAChRs are responsible for mediating nicotinic analgesia at supraspinal responses and spinal sites (Decker, M W, Rueter, L E and Bitner, R S (2004) Nicotinic acetylcholine receptor agonists: a potential new class of analgesics, Curr Top Med Chem., 4: 369-384). Antinociceptive effects through α4β2 nAChRs are generally attributed to stimulation of brainstem monoaminergic transmission, particularly in the raphe (Cucchiaro G, Chaijale N, and Commons K G (2005) J Pharmacol Exp Ther. 313:389-394). However, α4β2 stimulation of GABAergic and glycinergic inhibitory transmission in the spinal cord also may contribute (Rashid M H, Furue H, Yoshimura M, and Ueda H (2006) Pain 125:125-135).
Central α3* nAChRs may contribute to nicotinic analgesia (Khan I M, Wennerholm M, Singletary E, Polston K, Zhang L, Deerinck T, Yaksh T L, and Taylor P (2004) J Neurocytol. 33:543-556), but α3β4 ligands are of little interest because of likely autonomic side effects. Indeed, the goal has been to avoid α3* neuronal nicotinic receptor (NNR), as the dose-limiting emetic liability of nonselective compounds has been attributed to activation of α3 containing nAChRs. α3* nAChRs are expressed in the enteric nervous system as well as in other components of the peripheral and central nervous systems. Area postrema and nucleus tractus solitarius are brainstem nuclei thought to be involved in nausea and emesis. α3* nAChRs in the dorsal motor nucleus of the vagus and in nucleus tractus solitarius have been implicated in gastric and blood pressure responses to nicotine injected locally (Ferreira M, Singh A, Dretchen K L, Kellar K J, and Gillis R A (2000) J. Pharmacol. Exp. Ther. 294:230-238).
Compounds with varying degrees of selectivity for α4β2 nAChRs over other nicotinic subtypes (α3, α7, α1-containing) have been discovered over the years. For example, ABT-594 (referred to as Compound A in this application) was efficacious across a number of rodent models of nociception including acute thermal, chemogenic, neuropathic, and visceral pain (Decker M W, Meyer M D, and Sullivan J P (2001) Expert Opinion on Investigational Drugs 10:1819-1830). Available data suggest that ligands with selectivity for the α4β2 nAChRs over α3β4 efficacy is preferred for low adverse event profiles. In theory, the therapeutic index could be expanded by (a) reducing α3β4 activity or (b) increasing α4β2 efficacy without increasing α3β4 activity. The latter may be achieved by an α4β2 selective positive allosteric modulator (PAM) either alone or in combination with exogenous α4β2 agonist. Positive allosteric modulators can potentiate effects by enhancing the efficacy and or potency of agonists. Accordingly, an α4β2 selective positive allosteric modulator can selectively enhance effects at the preferred α4β2 nAChRs over other nAChR subtypes.
Initially known positive allosteric modulators of the α4β2 nAChRs have been nonselective and not very potent. For example, nefiracetam has been reported to potentiate α4β2 nAChR responses (Narahashi T, Moriguchi S, Zhao X, Marszalec W, and Yeh J Z (2004) Biol. Pharm. Bull. 27:1701-1706). More recently, subtype selective PAMs have been disclosed. Compounds like 3-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)benzonitrile and others have been described with robust α4β2 PAM effects with little modulatory activity at other subtypes such as α3β4 (e.g., see WO 2006/114400, published Nov. 2, 2006).
Pain is an unmet medical need and the methods and possibilities for treatments of such indications are insufficient. Although continued efforts are being made to treat pain using nAChR agonists, robust efficacy in pain may be limited by the range of side effects associated with their use, albeit to differing degrees. In light of the significance of chronic pain and the limitations in their treatment, it would be beneficial to identify new methods of treating such disorders, particularly in a manner that reduces adverse ganglionic effects such as at the gastrointestinal systems (e.g. emesis). It would be particularly beneficial to identify compounds and compositions that offer an opportunity to wide the therapeutic window of nicotinic (nAChR) agonists in pain. Enhanced efficacy with nAChR ligands for the treatment of other central nervous system diseases such as cognitive and attention deficits is also desirable.